HSV type 1 is a major cause of severe sporadic encephalitis in man. The epidemiology, clinical presentation, natural history, pathology and treatment of this disorder are characterized in the literature. The early symptoms and signs of HSV encephalitis, including personality change, behavioral disturbance, seizures and mutism, are anatomically explained by the predilection for the infectious process to involve early the medial temporal lobe, orbital frontal lobe and other "limbic" areas of the brain. Although late in the disease, destruction of these and other areas readily explains the severe sequelae in survivors, early in the illness, when diagnosis and institution of therapy are of paramount importance, symptoms and signs may be due to reversible physiological disturbance. It is on this phase of infection that the present invention is directed. For it is during this phase that conversion of a limited number of cells to virus-directed metabolism, in concert with secondary host responses, may lead to breakdown in the integrated reception, conduction and transmission of neural signals, not only in the immediate focus of infection, but beyond, within anatomically and functionally related regions of brain, resulting in the production of negative (loss of function) or positive (seizures) neurological manifestations.
A major impediment to effective management of HSV encephalitis is the lack of a reliable, non-invasive test which will allow early diagnosis. Unfortunately, present neurodiagnostic studies such as CT and radionuclide scanning may yield normal results early in the disease while viral serology is only retrospectively useful, and even then may not be definitive. At present, brain biopsy is the only definitive means of early diagnosis and this can cause brain damage in its use. Because of the drawbacks of known diagnostic methods, the clinician is left with a difficult decision which may result in delayed or inappropriate therapy. Clearly there is a need for an improved non-invasive diagnostic method such as provided by this invention.
The development of genuinely effective therapy for HSV encephalitis has made a non-invasive early diagnostic method even more useful than before such treatment was available. Thus, because the demonstration by the NIAID Collaborative Study that ara-A is less than optimal, newer, potentially more effective, drugs are currently being developed and tested including several drugs which exploit the virus-coded thymidine kinase (TK) and DNA polymerase enzymes to achieve specificity of antiviral effect. These include the very effective anti-viral pyrimidine nucleoside compounds disclosed in U.S. Pat. No. 4,211,773 to Lopez et al (see also Lopez et al. Antimicrob Agents Chemother 17: 803-806 (1980); Fox, J.J. et al. In Medicinal Chemistry Advances, FG DELAS HERAS, S VEGA (Eds), Pergamon Press, Elmsford, NY, p. 27-40 (1981); Watanabe et al. J MED. CHEM 22: 21-24, (1979). The availability of such new therapies renders early diagnosis all the more pressing since the stage of disease at which therapy is instituted appears very likely to determine the quality of outcome.
The present invention provides a non-invasive, accurate diagnostic test for HSV-1 encephalitis.